HPM2_HYPSB
ID HPM2_HYPSB Reviewed; 212 AA.
AC B3FWR8;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2008, sequence version 1.
DT 03-AUG-2022, entry version 49.
DE RecName: Full=Glutathione S-transferase hmp2 {ECO:0000303|PubMed:18567690};
DE EC=2.5.1.18 {ECO:0000269|PubMed:18567690};
DE AltName: Full=Hypothemycin biosynthesis cluster protein hpm2 {ECO:0000303|PubMed:18567690};
GN Name=hpm2 {ECO:0000303|PubMed:18567690};
OS Hypomyces subiculosus (Nectria subiculosa).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Hypocreaceae; Hypomyces.
OX NCBI_TaxID=193393;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, PATHWAY, AND CATALYTIC
RP ACTIVITY.
RC STRAIN=DSM11931, and DSM11932;
RX PubMed=18567690; DOI=10.1128/aem.00478-08;
RA Reeves C.D., Hu Z., Reid R., Kealey J.T.;
RT "Genes for the biosynthesis of the fungal polyketides hypothemycin from
RT Hypomyces subiculosus and radicicol from Pochonia chlamydosporia.";
RL Appl. Environ. Microbiol. 74:5121-5129(2008).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=10598882; DOI=10.1016/s0162-3109(99)00085-5;
RA Camacho R., Staruch M.J., DaSilva C., Koprak S., Sewell T., Salituro G.,
RA Dumont F.J.;
RT "Hypothemycin inhibits the proliferative response and modulates the
RT production of cytokines during T cell activation.";
RL Immunopharmacology 44:255-265(1999).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=10595743; DOI=10.1111/j.1349-7006.1999.tb00688.x;
RA Tanaka H., Nishida K., Sugita K., Yoshioka T.;
RT "Antitumor efficacy of hypothemycin, a new Ras-signaling inhibitor.";
RL Jpn. J. Cancer Res. 90:1139-1145(1999).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=10421424; DOI=10.1016/s0024-3205(99)00259-3;
RA Sonoda H., Omi K., Hojo K., Nishida K., Omura S., Sugita K.;
RT "Suppression of oncogenic transformation by hypothemycin associated with
RT accelerated cyclin D1 degradation through ubiquitin-proteasome pathway.";
RL Life Sci. 65:381-394(1999).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=18571434; DOI=10.1016/j.jsb.2008.05.002;
RA Rastelli G., Rosenfeld R., Reid R., Santi D.V.;
RT "Molecular modeling and crystal structure of ERK2-hypothemycin complexes.";
RL J. Struct. Biol. 164:18-23(2008).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=20118535; DOI=10.1248/bpb.33.168;
RA Fukazawa H., Ikeda Y., Fukuyama M., Suzuki T., Hori H., Okuda T.,
RA Uehara Y.;
RT "The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-
RT activated protein kinase kinase-extracellular signal-regulated kinase
RT pathway in cells.";
RL Biol. Pharm. Bull. 33:168-173(2010).
RN [7]
RP FUNCTION.
RX PubMed=20222707; DOI=10.1021/ja100060k;
RA Zhou H., Qiao K., Gao Z., Meehan M.J., Li J.W., Zhao X., Dorrestein P.C.,
RA Vederas J.C., Tang Y.;
RT "Enzymatic synthesis of resorcylic acid lactones by cooperation of fungal
RT iterative polyketide synthases involved in hypothemycin biosynthesis.";
RL J. Am. Chem. Soc. 132:4530-4531(2010).
RN [8]
RP BIOTECHNOLOGY.
RX PubMed=23853713; DOI=10.7554/elife.00712;
RA Nishino M., Choy J.W., Gushwa N.N., Oses-Prieto J.A., Koupparis K.,
RA Burlingame A.L., Renslo A.R., McKerrow J.H., Taunton J.;
RT "Hypothemycin, a fungal natural product, identifies therapeutic targets in
RT Trypanosoma brucei [corrected].";
RL Elife 2:E00712-E00712(2013).
RN [9]
RP BIOTECHNOLOGY.
RX PubMed=24106914; DOI=10.1021/jf4030882;
RA Xu L., Xue J., Wu P., Wang D., Lin L., Jiang Y., Duan X., Wei X.;
RT "Antifungal activity of hypothemycin against Peronophythora litchii in
RT vitro and in vivo.";
RL J. Agric. Food Chem. 61:10091-10095(2013).
RN [10]
RP BIOTECHNOLOGY.
RX PubMed=26371861; DOI=10.1016/j.intimp.2015.08.030;
RA Park K.H., Yoon Y.D., Kang M.R., Yun J., Oh S.J., Lee C.W., Lee M.Y.,
RA Han S.B., Kim Y., Kang J.S.;
RT "Hypothemycin inhibits tumor necrosis factor-alpha production by
RT tristetraprolin-dependent down-regulation of mRNA stability in
RT lipopolysaccharide-stimulated macrophages.";
RL Int. Immunopharmacol. 29:863-868(2015).
CC -!- FUNCTION: Glutathione S-transferase; part of the gene cluster that
CC mediates the biosynthesis of hypothemycin, a resorcylic acid lactone
CC (RAL) that irreversibly inhibits a subset of protein kinases with a
CC conserved cysteine in the ATP binding site such as human ERK2
CC (PubMed:18567690). The first step is performed by both PKSs hmp3 and
CC hmp8 and leads to the production of 7',8'-dehydrozearalenol (DHZ)
CC (PubMed:18567690, PubMed:20222707). The highly reducing PKS hpm8
CC synthesizes the reduced hexaketide (7S,11S,2E,8E)-7,11-dihydroxy-
CC dodeca-2,8-dienoate, which is transferred downstream to the non-
CC reducing PKS hpm3 (PubMed:20222707). Hpm3 then extends the reduced
CC hexaketide to a nonaketide, after which regioselective cyclization and
CC macrolactonization affords DHZ (PubMed:20222707). The next step is the
CC conversion of DHZ into aigialomycin C and is performed by the O-
CC methyltransferase hmp5, the FAD-binding monooxygenase hmp7, and the
CC cytochrome P450 monooxygenase hmp1 (PubMed:18567690). The wide
CC substrate tolerance of the hmp5 and hmp7 implies that the reactions
CC from DHZ to aigialomycin C can occur in any order (PubMed:18567690).
CC The steps from aigialomycin C to hypothemycin are less well established
CC (PubMed:18567690). The FAD-linked oxidoreductase hmp9 presumably
CC catalyzes oxidation of the C-6' hydroxyl to a ketone (PubMed:18567690).
CC The timing of this oxidation is important, since the resulting enone
CC functional group is a Michael acceptor that can react spontaneously
CC with glutathione, an abundant metabolite in fungal cells
CC (PubMed:18567690). The glutathione S-transferase hmp2 catalyzes cis-
CC trans isomerization of the 7',8' double bond with equilibrium favoring
CC the trans isomer (PubMed:18567690). The hpm6-encoded transporter might
CC preferentially pump hypothemycin out of the cell relative to the trans
CC isomer aigialomycin A. The cis-to-trans isomerization may be coupled
CC with C-4' hydroxylation, since all known hypothemycin analogs
CC containing the enone functional group also have hydroxyl groups at both
CC C-4' and C-5' (PubMed:18567690). {ECO:0000269|PubMed:18567690,
CC ECO:0000269|PubMed:20222707}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glutathione + RX = a halide anion + an S-substituted
CC glutathione + H(+); Xref=Rhea:RHEA:16437, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16042, ChEBI:CHEBI:17792, ChEBI:CHEBI:57925,
CC ChEBI:CHEBI:90779; EC=2.5.1.18;
CC Evidence={ECO:0000269|PubMed:18567690};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:18567690}.
CC -!- BIOTECHNOLOGY: Hypothemycin is an antifungal agent that exhibits
CC excellent activity against Peronophythora litchii, which could be
CC helpful for the storage of harvest litchi fruit (PubMed:24106914).
CC Hypothemycin is a strong inhibitor of a subset of MAP kinases such as
CC human ERK2 (PubMed:18571434, PubMed:20118535, PubMed:26371861). It can
CC therefore be used as an anti-cancer drug thanks to its inhibitory
CC activity of Ras-mediated cellular signals (PubMed:10595743,
CC PubMed:10421424). It can also inhibit Trypanosoma brucei kinase TbCLK1
CC which is a good candidate as a therapeutic target for African
CC trypanosomiasis (PubMed:23853713). Finally, hypothemycin has also
CC inhibitor activity of T cell activation (PubMed:10598882).
CC {ECO:0000269|PubMed:10421424, ECO:0000269|PubMed:10595743,
CC ECO:0000269|PubMed:10598882, ECO:0000269|PubMed:18571434,
CC ECO:0000269|PubMed:20118535, ECO:0000269|PubMed:23853713,
CC ECO:0000269|PubMed:24106914, ECO:0000269|PubMed:26371861}.
CC -!- SIMILARITY: Belongs to the GST superfamily. {ECO:0000305}.
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DR EMBL; EU520417; ACD39752.1; -; Genomic_DNA.
DR EMBL; EU520418; ACD39761.1; -; Genomic_DNA.
DR AlphaFoldDB; B3FWR8; -.
DR SMR; B3FWR8; -.
DR GO; GO:0004364; F:glutathione transferase activity; IEA:UniProtKB-EC.
DR GO; GO:0006749; P:glutathione metabolic process; IEA:InterPro.
DR InterPro; IPR010987; Glutathione-S-Trfase_C-like.
DR InterPro; IPR036282; Glutathione-S-Trfase_C_sf.
DR InterPro; IPR040079; Glutathione_S-Trfase.
DR InterPro; IPR004045; Glutathione_S-Trfase_N.
DR InterPro; IPR004046; GST_C.
DR InterPro; IPR036249; Thioredoxin-like_sf.
DR Pfam; PF00043; GST_C; 1.
DR Pfam; PF02798; GST_N; 1.
DR SFLD; SFLDS00019; Glutathione_Transferase_(cytos; 1.
DR SUPFAM; SSF47616; SSF47616; 1.
DR SUPFAM; SSF52833; SSF52833; 1.
DR PROSITE; PS50405; GST_CTER; 1.
DR PROSITE; PS50404; GST_NTER; 1.
PE 1: Evidence at protein level;
KW Transferase.
FT CHAIN 1..212
FT /note="Glutathione S-transferase hmp2"
FT /id="PRO_0000437598"
FT DOMAIN 1..80
FT /note="GST N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00684"
FT DOMAIN 88..212
FT /note="GST C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00685"
FT BINDING 51..52
FT /ligand="glutathione"
FT /ligand_id="ChEBI:CHEBI:57925"
FT /evidence="ECO:0000250|UniProtKB:P08263"
FT BINDING 64..65
FT /ligand="glutathione"
FT /ligand_id="ChEBI:CHEBI:57925"
FT /evidence="ECO:0000250|UniProtKB:P08263"
SQ SEQUENCE 212 AA; 24145 MW; BACC065A187926EF CRC64;
MVIKLYGSAM STARVLVTLL EKELPYEHIL VDISKGDQNK EEYLKLQPFG KVPVLDDNGF
IMYESRAICR YLARKYDSGT KLIPDVDDHE AYGRFEQGCS IEYSYFAAAA ETLGTELVIK
KYKGLGEPDM TRVAQAEADF DKVFFEYDKI LAKQKYLTGD EISLVDLFHL PNASALKAFG
YQGTFEKYPN VNRWFSGLQA RETWIKATAE AR
